Browsing by Author "Masimirembwa, Collen"

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    A cost effective RFLP method to genotype Solute carrier organic anion 1B1 (SLCO1B1) c.1929A>C (p.Leu643Phe, rs34671512); a variant with potential effect on rosuvastatin pharmacokinetics
    (BioMed Central, 2018-06-14) Soko, Nyarai D; Masimirembwa, Collen; Dandara, Collet
    Objective: This study describes a restriction fragment polymorphism protocol for rapidly screening the polymorphism SLCO1B1 c.1929A>C in genomic DNA samples. The polymorphism SLCO1B1 c.1929A>C has been associated with increased activity resulting in increased hepatic uptake of drugs. Currently SLCO1B1 c.1929A>C is genotyped using direct sequencing techniques and 5′ nuclease based assays which can be cost prohibiting in resource limited settings. The aim of this study therefore was to design and validate a cost effective RFLP for genotyping the SLCO1B1 c.1929A>C polymorphism. This study was designed to investigate the effect of the polymorphism SLCO1B1 c.1929A>C on interindividual variability in rosuvastatin pharmacokinetics in healthy volunteers of African descent. Results We describe a restriction fragment length polymorphism method to genotype SLCO1B1 c.1929A>C polymorphism using the restriction enzyme Ase1. A student’s t test with Welch correction was used to establish association between the SLCO1B1 c.1929A>C variant and rosuvastatin exposure. The frequency of the SLCO1B1 c.1929C allele amongst Zimbabweans was 6%. The SLCO1B1 c.1929C allele was associated with a 75% reduction (P < 0.001) in rosuvastatin exposure when compared to individuals carrying the wild type SLCO1B1 c.1929A allele. Polymorphism c.1929A>C may therefore play a significant role in rosuvastatin response. The RFLP method is quick and cost effective.
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    Antimalarial drug rescue through safety improvement: design, synthesis and evaluation of amaodiaquine analogues
    (2014) Ongarora, Dennis Sure Bagwasi; Chibale, Kelly; Masimirembwa, Collen
    Malaria is a major cause of morbidity and mortality globally, resulting in over 200 million cases and 650, 000 deaths in 2010 according to the 2012 WHO Malaria Report. Furthermore, malaria endemicity is associated with poor economic growth. One of the greatest challenges facing malaria chemotherapy is the emergence of Plasmodium strains resistant to all known clinically used antimalarials. This underscores the need for the development of new drugs that retain efficacy against the resistant parasites. In this study, analogue-based drug design was employed as a form of drug ‘rescue’ in the development of novel potential antimalarials. The main aim was to design and synthesize analogues of the 4-aminoquinoline drug amodiaquine with potentially improved safety and efficacy profiles using prior knowledge of the drug metabolism and pharmacokinetics (DMPK), toxicity and efficacy profile of the drug. A representative set of compounds in four different series was synthesized in which the 4-aminoquinoline ring was coupled with benzothiazole, benzimidazole, benzoxazole and pyridyl rings bearing different aliphatic amines and diamines. The chemistry involved aromatic nucleophilic substitution reactions and hydrogenation of nitro aromatic compounds. Benzothiazole and benzoxazole analogues with a tertiary protonatable nitrogen were found to possess potent antiplasmodial activity against the drug resistant W2 and K1 Plasmodium falciparum strains.
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    Integration of In Silico and In Vitro ADMET properties in lead identification and optimization of compounds for the treatment of parasitic diseases
    (2012) Thelingwani, Roslyn; Chibale, Kelly; Masimirembwa, Collen; Smith, Peter
    Parasitic infections are the major causes of illness and death in tropical regions especially in Africa. The main parasitic diseases include leishmaniasis, filariasis, malaria, river blindness, Chagas disease and schistosomiasis. With the absence of vaccines, treatment relies mainly on chemotherapy hence the need for efficacious and safe medicines. Many of the medicines currently used have low efficacy and cause side effects. Some are also being lost to drug resistance. To address the inadequacy of treatment options for infectious diseases, a number of initiatives have been started to promote drug discovery and development in Africa. In parallel they have been collaboration between African institutions and leading pharmaceutical companies as well as other relevant R & D organizations. This has led to the need to modernize African approaches to drug discovery and development with respect to the integration of medicinal chemistry, pharmacology and pharmacokinetics as reflected in the processes of Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET). However, scientific and technological expertise in pharmacokinetics for drug discovery is under developed in Africa.
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    Novel variants of major drug-metabolising enzyme genes in diverse African populations and their predicted functional effects
    (BioMed Central Ltd, 2009) Matimba, Alice; Del-Favero, Jurgen; Van Broeckhoven, Christine; Masimirembwa, Collen
    Pharmacogenetics enables personalised therapy based on genetic profiling and is increasingly applied in drug discovery. Medicines are developed and used together with pharmacodiagnostic tools to achieve desired drug efficacy and safety margins. Genetic polymorphism of drug-metabolising enzymes such as cytochrome P450s (CYPs) and N-acetyltransferases (NATs) has been widely studied in Caucasian and Asian populations, yet studies on African variants have been less extensive. The aim of the present study was to search for novel variants of CYP2C9, CYP2C19, CYP2D6 and NAT2 genes in Africans, with a particular focus on their prevalence in different populations, their relevance to enzyme functionality and their potential for personalised therapy. Blood samples from various ethnic groups were obtained from the AiBST Biobank of African Populations. The nine exons and exon-intron junctions of the CYP genes and exon 2 of NAT2 were analysed by direct DNA sequencing. Computational tools were used for the identification, haplotype analysis and prediction of functional effects of novel single nucleotide polymorphisms (SNPs). Novel SNPs were discovered in all four genes, grouped to existing haplotypes or assigned new allele names, if possible. The functional effects of non-synonymous SNPs were predicted and known African-specific variants were confirmed, but no significant differences were found in the frequencies of SNPs between African ethnicities. The low prevalence of our novel variants and most known functional alleles is consistent with the generally high level of diversity in gene loci of African populations. This indicates that profiles of rare variants reflecting interindividual variability might become the most relevant pharmacodiagnostic tools explaining Africans' diversity in drug response.
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    Pharmacogenetics of African populations : variation in major drug metabolising enzyme genes and potential impact on personalised medicine.
    (2009) Matimba, Alice; Ramesar, Raj; Masimirembwa, Collen
    Includes bibliographical references (leaves 167-200)
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    The Next Generation Scientist program: capacity-building for future scientific leaders in low- and middle-income countries
    (BioMed Central, 2018-10-10) Pillai, Goonaseelan; Chibale, Kelly; Constable, Edwin C; Keller, Akiko N; Gutierrez, Marcelo M; Mirza, Fareed; Sengstag, Christian; Masimirembwa, Collen; Denti, Paolo; Maartens, Gary; Ramsay, Michèle; Ogutu, Bernhards; Makonnen, Eyasu; Gordon, Richard; Ferreira, Carlos G; Goldbaum, Fernando A; Degrave, Wim M S; Spector, Jonathan; Tadmor, Brigitta; Kaiser, Hedwig J
    Background Scientific and professional development opportunities for early career scientists in low- and middle- income countries (LMICs) are limited and not consistent. There is a disproportionately low number of biomedical and clinical researchers in LMIC’s relative to their high burden of disease, a disparity that is aggravated by emigration of up to 70% of scientists from their countries of birth for education and employment elsewhere. To help address this need, a novel University-accredited, immersive fellowship program was established by a large public-academic-private network. We sought to describe the program and summarize progress and lessons learned over its first 7-years. Methods Hallmarks of the program are a structured learning curriculum and bespoke research activities tailored to the needs of each fellow. Research projects expose the scientists to state-of-the-art methodologies and leading experts in their fields while also ensuring that learnings are implementable within their home infrastructure. Fellows run seminars on drug discovery and development that reinforce themes of scientific leadership and teamwork together with practical modules on addressing healthcare challenges within their local systems. Industry mentors achieve mutual learning to better understand healthcare needs in traditionally underserved settings. We evaluated the impact of the program through an online survey of participants and by assessing research output. Results More than 140 scientists and clinicians from 25 countries participated over the 7-year period. Evaluation revealed strong evidence of knowledge and skills transfer, and beneficial self-reported impact on fellow’s research output and career trajectories. Examples of program impact included completion of post-graduate qualifications; establishment and implementation of good laboratory- and clinical- practice mechanisms; and becoming lead investigators in local programs. There was a high retention of fellows in their home countries (> 75%) and an enduring professional network among the fellows and their mentors. Conclusions Our experience demonstrates an example for how multi-sectoral partners can contribute to scientific and professional development of researchers in LMICs and supports the idea that capacity-building efforts should be tailored to the specific needs of beneficiaries to be maximally effective. Lessons learned may be applied to the design and conduct of other programs to strengthen science ecosystems in LMICs.